Solubilizing of metronidazole

ABSTRACT

Metronidazole is solubilized in an aqueous phase, by mixing same with niacinamide and at least two glycolic cosolvents; the resulting solutions and pharmaceutical compositions comprised thereof are useful for the treatment of dermatological conditions/afflictions, notably rosacea.

CROSS-REFERENCE TO PRIORITY/PCT APPLICATIONS

This application claims priority under 35 U.S.C. §119 of FR 05/06182,filed Jun. 17, 2005, and is a continuation of PCT/FR 2006/001367, filedJun. 16, 2006 and designating the United States (published in the Frenchlanguage on Dec. 21, 2006 as WO 2006/134279 A2; the title and abstractwere also published in English), each hereby expressly incorporated byreference in its entirety and each assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to the formulation of bioactiveingredients for the purpose of pharmaceutical applications, inparticular for topical application/administration.

The present invention relates, in particular, to a novel process forsolubilizing metronidazole in a pharmaceutical composition, bycombining, in an aqueous phase, at least metronidazole, niacinamide,propylene glycol and polyethylene glycol. Such combinations make itpossible to solubilize the metronidazole therein.

This invention also relates to the solutions/compositions formulated viathe subject solubilization process, to the method for preparing same, tothe resulting compositions containing the metronidazole thussolubilized, and to the administration thereof in human or veterinarymedicine.

2. Description of Background and/or Related and/or Prior Art

Metronidazole, or 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, has longbeen known as a bioactive compound in the treatment of variousconditions and afflictions, and in particular in the treatment ofdiseases due to various protozoa. When applied topically, metronidazoleis also used in the treatment of various dermatological conditions,including rosacea (acne rosacae), bacterial ulcers and perioraledermatitis, as described in U.S. Pat. No. 4,837,378. Metronidazole alsoexhibits an anti-inflammatory activity when it is applied topically inthe treatment of dermatological disorders, as described in U.S. Pat. No.5,849,776. Metronidazole can also be used in the treatment of bacterialvaginosis, as an intravaginal therapeutic agent, as described in U.S.Pat. No. 5,536,743.

The compositions containing metronidazole for the treatment ofdermatological disorders/afflictions are available in the form of acream, a gel or a lotion. Noritate™ (Dermik Laboratories, Inc.) contains1% of metronidazole dispersed in a white cream. Galderma Laboratories,Inc proposes MetroGel®, containing 0.75% by mass, relative to the totalmass of the composition (m/m), of metronidazole solubilized in atransparent gel, MetroCream® containing 0.75% (m/m) of metronidazolesolubilized in an emollient cream, and MetroLotion® containing 0.75%(m/m) of metronidazole solubilized in a lotion.

In the case of topical applications, products containing the activeingredient in solubilized form often exhibit better bioavailability thanproducts in which the active ingredient is dispersed.

Given the low intrinsic solubility of metronidazole in an aqueous phase,which is on the order of 0.9% (m/m), the gelled aqueous compositionscurrently available on the market are limited to a concentration of0.75% (m/m) of metronidazole, solubilized in the formulation. Themetronidazole formulations in the form of creams have the advantage,over the gelled formulations currently available, of containing 1% (m/m)of metronidazole.

In general, the solubility of the active ingredients in an aqueous phasemay be increased by including various non-ionic or ionic surfactants,lipid derivatives such as lecithins which allow the formation of lipidmicelles, or cyclodextrins as often described in the literature.

Cyclodextrins make it possible to increase the water-solubility ofvarious compounds. Cyclodextrins are in the form of a cage. Thehydrophilic external part of this cage confers on them a certainsolubility in aqueous media. Their inner part, which is morehydrophobic, allows the solubilization of amphiphilic or lipophilicmolecules through the formation of inclusion complexes. Thewater-solubility of many molecules can therefore be substantiallyincreased by employing these cyclodextrins. However, cyclodextrins havedrawbacks in terms of cost, of limited solubility, of incompatibilitywith certain carriers or excipients, or of potential local or systemictoxicity. Furthermore, the formation of the inclusion complexes,complexation step, can be quite long, commonly several hours, and canaffect the costs and processes for manufacturing the formulations.

Solubility-increasing agents other than cyclodextrins have beendescribed. Yie W. Chien, Journal of Parenteral Science and Technology,38 (1): 32-36 (January 1984), shows that the solubility of metronidazolein an aqueous solution can be increased by means of water-solublevitamins such as niacinamide, pyridoxine hydrochloride and ascorbicacid. Chien subsequently describes that the water-solubility ofmetronidazole increases in a linear manner in relation to theconcentration of these water-soluble vitamins in solution. Inparticular, Chien shows that it is necessary to have at least 9 mol ofniacinamide in solution in order to solubilize 1 mol of metronidazole.In particular, Chien has shown that a combination of niacinamide withmetronidazole in a molar ratio of 9 to 1 makes it possible to increasethe solubility of metronidazole in an aqueous phase. Thus, in order toobtain a formulation containing 1% (m/m) of metronidazole solubilized inthe aqueous phase, it is necessary to introduce a high niacinamidecontent on the order of 6.4% (m/m).

Y. Chang, G. Dow et al. describe in U.S. Pat. No. 6,468,989, on thebasis of the studies by Chien et al., the use of cyclodextrins incombination with niacinamide in order to formulate gels containing 1% ofmetronidazole (m/m) with a niacinamide content below that of the priorart, i.e., only 1.25% (m/m). They have demonstrated a synergistic effectof the niacinamide/cyclodextrins combination on metronidazolesolubility.

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that metronidazole can besolubilized in the absence of the solvents conventionally described inthe literature. More specifically, metronidazole has now beensolubilized in the absence of cyclodextrin or of surfactant, and in thepresence of a low niacinamide content.

The present invention thus features a novel process for solubilizingmetronidazole in an aqueous phase. This invention therefore features aprocess for solubilizing metronidazole in a composition free ofcyclodextrin or of surfactant and comprising a low niacinamide content.

The present invention also features aqueous solutions comprisingmetronidazole, niacinamide, at least two glycolic cosolvents, such aspropylene glycol and a polyethylene glycol, and water.

In a third embodiment, the present invention features pharmaceuticalcompositions comprising the above solutions.

According to a fourth embodiment, a solution or a pharmaceuticalcomposition according to the invention is administered as a medicamentfor the treatment of a dermatological condition, in particular rosacea,acne vulgaris or seborrhoeic dermatitis, and preferably rosacea.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

The process according to the invention makes it possible to solubilizemetronidazole in an aqueous phase at a concentration of greater than orequal to the concentration of 0.75% by mass relative to the total massof the solution (m/m) usually present in commercialized formulations,and more particularly at a concentration of greater than or equal to 1%(m/m).

The process for solubilizing metronidazole according to the inventiontherefore comprises the step which entails mixing the metronidazole withniacinamide, in particular in a small amount, in an aqueous phase, alongwith glycolic solvent compounds, preferably at least two, in the absenceof cyclodextrin and/or of surfactant.

The term “aqueous phase” means a phase composed predominantly of water.

The term “solubilization of metronidazole” means a dispersion in themolecular state in a liquid, no crystallization of the metronidazolebeing visible to the naked eye or even under a cross-polarizationoptical microscope.

According to the invention, the term “metronidazole” means metronidazoleas such, but also in the form of a salt with a pharmaceuticallyacceptable acid, or else in the form of an ester. An exemplary salt is,in particular, metronidazole hydrochloride. The term “esters” means inparticular metronidazole acetate, benzoate, myristate or monosuccinate.

According to the present invention, the niacinamide can be used as such,or else in the form of salts with a pharmaceutically acceptable acid.

Preferably, the niacinamide/metronidazole molar ratio employed in theprocess according to the invention is strictly less than 9, andpreferably less than or equal to 5.5.

According to the present invention and, surprisingly, it has noweffectively been demonstrated that the combination of 2 glycoliccosolvents in the presence of niacinamide makes it possible to increasethe solubility of metronidazole in an aqueous phase.

Among the glycolic solvents according to the present invention,particularly exemplary are propylene glycol, butylene glycol,ethoxydiglycol, butoxydiglycol and polyethylene glycols (PEGs).

More particularly, the glycolic cosolvents are propylene glycol and atleast one polyethylene glycol (PEG). The preferred PEGs are the liquidPEGs, such as PEGs 200; 300; 400; and 600.

Advantageously, a combination of 2 glycolic cosolvents is employed,which is a combination of propylene glycol with a polyethylene glycol(PEG). The preferred 2 cosolvents to be employed in combinationaccording to the present invention are propylene glycol and PEG 400.

Indeed, as shown by the results presented in Examples 1 and 2 below, inthe combination according to the invention, the propylene glycol, thePEG 400 and the niacinamide act in synergy to increase the aqueoussolubility and the physical stability of the metronidazole solutions. Inaddition, the propylene glycol/PEG 400 combination makes it possible toconsiderably reduce the niacinamide/metronidazole molar ratio.

Preferably according to the present invention, this increase insolubility of metronidazole in an aqueous phase is obtained through thecombination of 2 cosolvents, preferably propylene glycol/PEG 400,according to a ratio by mass of 1:1 in the presence of niacinamide.According to a preferred embodiment, the niacinamide/metronidazole molarratio can be reduced to 4. According to an even more preferredembodiment, the combination according to the invention makes it possibleto solubilize the metronidazole at least to a concentration of 1.56%(m/m), while at the same time having a niacinamide/metronidazole molarratio strictly less than 9.

Advantageously, the process for solubilizing metronidazole according tothe invention comprises, in particular, the following steps:

a) preparation of a solution of niacinamide, in particular at 10% (m/m)in water, until the niacinamide has completely dissolved. An amount ofthis solution is used, which amount depends, as previously indicated, onthe amount of metronidazole to be dissolved and on theniacinamide/metronidazole molar ratio previously defined,

b) introduction of the glycolic cosolvents, preferably two of them, intothe solution obtained in a),

c) after homogenization of the solution obtained in b), addition of adefined amount of metronidazole. This amount depends on theniacinamide/metronidazole molar ratio previously defined,

d) after complete dissolution of the metronidazole, filtration of thesolution obtained.

The metronidazole is then quantitatively determined in order to verifythe percentage solubilized.

Preferably, the two cosolvents used for the solubilization according tothe invention are propylene glycol and PEG 400.

Preferably, and in a manner that is in no manner limiting, the mixing iscarried out by mechanical stirring, the filtration is carried outthrough a 1 μm filter and the metronidazole is quantitatively determinedby measuring optical density by UV spectrophotometry at the wavelengthof 327 nm.

Without cyclodextrin, the solubilization technique according to theinvention is more advantageous since it does not require a complexationstep.

Without surfactant necessary for the solubilization, the compositioncontaining the metronidazole thus solubilized advantageously exhibits areduced risk of skin irritations or skin allergies.

This invention also features the aqueous solutions of metronidazole thatare obtained according to the process defined above.

The aqueous solutions according to the invention are characterized inthat they comprise:

metronidazole,

niacinamide,

at least 2 glycolic cosolvents, preferably 2, which are preferablypropylene glycol and a polyethylene glycol,

water.

Such solutions, comprising metronidazole in solubilized form, do notcontain, in particular, any cyclodextrin.

In the solutions according to the invention, the metronidazole ispresent at a concentration of greater than or equal to 0.75% (m/m),preferably greater than or equal to 1% (m/m).

The niacinamide in the solutions according to the invention is presentat a concentration such that the niacinamide/metronidazole molar ratiois strictly less than 9, preferably less than or equal to 5.5.

According to the invention, two glycolic cosolvents are preferablyemployed. The two glycolic cosolvents together, preferably propyleneglycol and a polyethylene glycol, have a total concentration of between2% and 50% (m/m), preferably between 5% and 20%, and more preferablyequal to 10% (m/m), it being understood that they are present in a ratioby mass of 1:1. Preferably according to the invention, the propyleneglycol and the polyethylene glycol are present in a ratio by mass of1:1, each at the concentration of 5% (m/m).

Preferably, the solutions according to the invention have all thefollowing properties:

metronidazole in a proportion greater than or equal to 1%,

niacinamide in a proportion such that the niacinamide/metronidazolemolar ratio is strictly less than 9, and preferably less than or equalto 5.5,

propylene glycol and a polyethylene glycol in a ratio by mass of 1:1,the polyethylene glycol preferably being PEG 400.

The present invention also features pharmaceutical compositionscomprising the above solutions. Such a composition comprisesmetronidazole in an amount of greater than or equal to 0.75% by weightrelative to the total weight of the composition, preferably greater thanor equal to 1% by weight relative to the total weight of thecomposition.

According to the present invention, the term “composition” means apharmaceutical composition more particularly for use in the treatment ofthe skin and the mucous membranes, whether regime or regimen, and whichcan be in liquid, pasty or solid form, and more particularly in the formof salves, creams, milks, ointments, powders, impregnated pads, syndets,solutions, lotions, gels, sprays, foams, suspensions, sticks, shampoosor washing bases. Same can also be in the form of suspensions ofmicrospheres or nanospheres or of lipid or polymeric vesicles or ofpolymeric or gelled patches for controlled release.

This invention also features the solutions and/or the compositionscomprising the metronidazole thus solubilized, as medicaments.

More particularly, this invention thus features the formulation of thesolutions and/or of the compositions comprising the metronidazole thussolubilized, into medicaments for the treatment of a dermatologicalcondition, in particular rosacea, acne vulgaris or seborrhoeicdermatitis. Preferably, the dermatological condition is rosacea.

Finally, the present invention features the use of a combination ofniacinamide and of at least two glycolic cosolvents, for solubilizingmetronidazole in a composition comprising an aqueous phase substantiallyfree of cyclodextrin.

The expression “aqueous phase substantially free of cyclodextrin” meansan aqueous phase which does not contain cyclodextrin.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative. Insaid examples to follow, all parts and percentages are given by weight,unless otherwise indicated.

EXAMPLE 1 Preparation of Solutions

In this example, all the metronidazole solubility tests are carried outusing a solution of niacinamide at 10% (m/m).

In the case of solutions containing 1% (m/m) of metronidazole withoutcosolvent: (solutions 1 to 3):

The metronidazole content is fixed at 1% (m/m).

According to the fixed niacinamide/metronidazole molar ratio, an amountof solution containing 10% of niacinamide is weighed out and is added tothe amount of metronidazole previously weighed out, and then the mixtureis made up to 100% through the addition of distilled water.

After magnetic stirring for 12 hours, the solution obtained is filteredthrough 1 μm and assayed by UV at the wavelength of 327 nm.

In the case of solutions containing 1% (m/m) of metronidazole withcosolvent: (solutions 4 to 6):

The metronidazole content is fixed at 1% (m/m) and theniacinamide/metronidazole molar ratio is fixed at 4.

Propylene glycol or PEG 400, alone or in combination, is/are added, asappropriate, to the amount of 10% (m/m) niacinamide solutioncorresponding to the molar ratio defined above. The metronidazole isthen weighed out and added to the solution obtained. An amount of wateris then added in order to make the mixture up to 100%.

After magnetic stirring for 12 hours, the solution obtained is filteredthrough 1 μm and assayed by UV at the wavelength of 327 nm.

In the case of solutions saturated with metronidazole: (solutions 7 and8):

The metronidazole content is fixed at 2% (m/m).

The propylene glycol and the PEG 400 are added, according to a ratio bymass of 1:1, to the amount of active ingredient previously weighed out.Depending on the case, the niacinamide in solution at 10% is added insuch a way as to observe the niacinamide/metronidazole molar ratio of 4.A required amount of water is then added in order to make the mixture upto 100%.

After magnetic stirring for 12 hours, the solution obtained is filteredthrough 1 μm and assayed by UV at the wavelength of 327 nm.

The following solutions were therefore prepared:

TABLE 1 Content Niacinamide/ Measured (% metronidazole concentrationSolutions Composition m/m) molar ratio (% m/m) No. 1 Metronidazole 1.010  1.016 Niacinamide 10% 71.3 Distilled water 27.7 No. 2 Metronidazole1.0 8 0.989 Niacinamide 10% 57.0 Distilled water 42.0 No. 3Metronidazole 1.0 4 1.023 Niacinamide 10% 28.5 Distilled water 70.5 No.4 Metronidazole 1.0 4 1.172 Niacinamide 10% 28.5 PEG 400 5.0 Distilledwater 65.5 No. 5 Metronidazole 1.0 4 1.185 Niacinamide 10% 28.5Propylene glycol 5.0 Distilled water 65.5 No. 6 Metronidazole 1.0 4 1.03Niacinamide 10% 28.5 Propylene glycol 5.0 PEG 400 5.0 Distilled water60.5 No. 7 Metronidazole 2.0 NA 0.998 Propylene glycol 5.0 PEG 400 5.0Distilled water 88.0 No. 8 Metronidazole 2.0 4 1.565 Niacinamide 10%57.0 Propylene glycol 5.0 PEG 400 5.0 Distilled water 31.0 —: no data

EXAMPLE 2 Stability Study

The solutions prepared according to Example 1 were monitored in terms ofstability over a period of 8 weeks at ambient temperature and at +4° C.Since the latter condition is more drastic, it makes it possible toreveal more rapidly the potential metronidazole recrystallizationphenomena.

The results obtained are the following:

TABLE II Stability at ambient Stability at +4° C. temperature (visualSolutions (visual observation) observation) No. 1 Clear Clear No. 2Precipitation at 13 days Clear No. 3 Precipitation at 5 days Clear No. 4Precipitation at 8 days Precipitation at 18 days No. 5 Precipitation at8 days Precipitation at 18 days No. 6 Clear Clear No. 7 Precipitation at8 days Precipitation at 8 days No. 8 Clear Clear

Conclusions:

The comparison of solutions 1 and 2 made it possible to confirm theresults of Chien et al., showing that it is necessary to introduceniacinamide into the aqueous solutions of metronidazole in order toincrease its solubility and its physical stability in an aqueous phase.The niacinamide/metronidazole molar ratio should be greater than 8 inorder to obtain a solution containing 1% (m/m) of metronidazole which isphysically stable for 8 weeks at ambient temperature and at +4° C.

The comparison of solutions 3; 4; 5 and 6 shows that it is necessary tointroduce the propylene glycol and the PEG 400 in combination accordingto a preferential ratio by mass of 1:1, in order to obtain a solutionthat is stable for 8 weeks at +4° C. and at ambient temperature. Byvirtue of this combination, the niacinamide/metronidazole molar ratiocould be reduced to 4.

The comparison of solutions 7 and 8 shows the need to introduceniacinamide into the ternary mixture of water/propylene glycol/PEG 400in order to obtain a solution that is stable over a period of 8 weeks at+4° C. and at ambient temperature.

The presence of the niacinamide in a solution saturated withmetronidazole makes it possible to increase the solubility of the activeingredient at least up to 1.5% (m/m) without recrystallization (solution8).

As a complement to the studies by Chien et al., this study also showsthat the niacinamide/metronidazole molar ratio initially of 9 can bereduced by a factor of 2 in the presence of propylene glycol and PEG400, preferably combined according to a ratio by mass of 1:1.

The results of this study therefore make it possible to envisage theformulation of metronidazole solubilized at 1% (m/m) with a niacinamidecontent of much less than 6.4 (m/m) without the use of cyclodextrins orof additional surfactants in the composition.

EXAMPLE 3 Example of a Composition Containing Metronidazole at 1% (m/m)

a) Lotion at 1% (m/m): Ingredients Formula (% m/m) Metronidazole 1.00Niacinamide 2.85 Propylene glycol 5.00 Macrogol 400 (PEG 400) 5.00Benzyl alcohol 1.30 Glycerol 5.00 Stearyl alcohol 2.00 Mineral oil 6.00Carbomer 981 NF 0.15 Arlacel 165 FL 3.00 Potassium sorbate 0.20Cyclomethicone 4.00 Steareth 21 3.00 10% Sodium hydroxide qs pH 5.0 ±0.5 Purified water qs 100.00

The lotion is prepared according to the following procedure:

Aqueous Phase:

1) The water is weighed out into a beaker and the niacinamide, theMacrogol 400, the propylene glycol and the metronidazole are introducedwith stirring using a deflocculator (300 rpm).

2) After complete dissolution of the metronidazole, the glycerol, theCarbomer 981 and the Steareth 21 are added.

3) The aqueous phase is heated to 70° C.

Fatty Phase:

1) The stearyl alcohol, the mineral oil and the Arlacel 165 FL areweighed out into a beaker.

2) The mixture is heated to 70° C. and stirred using a deflocculator(300 rpm).

Emulsification:

1) The fatty phase is gently introduced into the aqueous phase withvigorous stirring (900 rpm) using a stator rotor while maintaining thetemperature at 70° C.

2) After introduction, the mixture is left to stir for 10 minutes.

3) The mixture is left to cool to ambient temperature with gentlerstirring (300 rpm) and the cyclomethicone, the benzyl alcohol and thepotassium sorbate are introduced.

4) The pH is adjusted with a 10% (m/m) sodium hydroxide solution ifnecessary.

5) The mixture is made up with water and homogenized if there has beenevaporation of the water during emulsification.

b) Gel at 1% (m/m): Ingredients Formula (% m/m) Metronidazole 1.00Niacinamide 2.85 Propylene glycol 5.00 Macrogol 400 (PEG 400) 5.00Disodium edetate (EDTA) 0.10 Carbomer 980NF 0.50 Methylpara-hydroxybenzoate 0.15 Propyl para-hydroxybenzoate 0.05 10% Sodiumhydroxide qs pH 5.0 ± 0.5 Purified water qs 100.00

The gel is prepared according to the following procedure:

1) The water is weighed out into a beaker and the niacinamide, theMacrogol 400, the propylene glycol and the metronidazole are introducedwith stirring using a deflocculator (300 rpm).

2) After complete dissolution of the metronidazole, the Carbomer 980NFand the EDTA are added and the mixture is heated to 60° C. andhomogenized using a deflocculator (600 rpm).

3) The mixture is left to cool to ambient temperature and the parabensare added, and the mixture is homogenized until complete dissolution isobtained (600 rpm).

4) The pH is adjusted using a 10% (m/m) sodium hydroxide solution ifnecessary.

5) The mixture is made up with water and homogenized if there has beenevaporation.

c) Cream at 1% (m/m): Ingredients Formula (% m/m) Metronidazole 1.00Niacinamide 2.85 Propylene glycol 5.00 Macrogol 400 (PEG 400) 5.00Benzyl alcohol 2.20 Isopropyl myristate 2.00 Glycerol 4.00 Polawax NF12.50  90% Lactic acid qs pH 5.0 ± 0.5 Purified water qs 100.00The cream is prepared according to the following procedure:

Aqueous Phase:

1) The water is weighed out into a beaker and the niacinamide, theMacrogol 400, the propylene glycol and the metronidazole are introducedwith stirring using a deflocculator (300 rpm).

2) After complete dissolution of the metronidazole, the glycerol isadded.

3) The aqueous phase is heated to 70° C.

Fatty Phase:

1) The isopropyl myristate and the Polawax NF are weighed out into abeaker.

2) The mixture is heated to 70° C. and stirred using a deflocculator(300 rpm).

Emulsification:

1) The fatty phase is gently introduced into the aqueous phase withvigorous stirring (900 rpm) using a stator rotor while maintaining thetemperature at 70° C.

2) After introduction, the mixture is left to stir for 10 minutes.

3) The mixture is left to cool to ambient temperature with gentlerstirring (300 rpm) and the benzyl alcohol is introduced.

4) The pH is adjusted with a 90% lactic acid solution if necessary.

5) The mixture is completed with water and homogenized if there has beenevaporation of water during the emulsification.

d) Spray at 1% (m/m): Ingredients Formula (% m/m) Metronidazole 1.00Niacinamide 2.85 Propylene glycol 5.00 Macrogol 400 (PEG 400) 5.00Xanthan gum 1.00 Benzyl alcohol 2.00 Ethanol 30.00  Purified water qs100.00

The spray is prepared according to the following procedure:

1) The water is weighed out into a beaker and the niacinamide, theMacrogol 400, the propylene glycol and the metronidazole are introducedwith stirring using a deflocculator (300 rpm).

2) After complete dissolution of the metronidazole, the xanthan gum isadded and the mixture is heated to 60° C. and left to homogenize (600rpm).

3) After complete dissolution of the xanthan gum, the mixture is left tocool to ambient temperature and the ethanol and the benzyl alcohol areadded.

4) The mixture is homogenized until a clear solution is obtained (300rpm)

EXAMPLE 4 Examples of Compositions Containing Metronidazole atConcentrations Greater Than 1% (m/m)

a) Gel at 1.5% (m/m): Ingredients Formula (% m/m) Metronidazole 1.50Niacinamide 5.70 Propylene glycol 5.00 Macrogol 400 (PEG 400) 5.00Disodium edetate (EDTA) 0.10 Carbomer 940 0.60 Methylpara-hydroxybenzoate 0.15 Propyl para-hydroxybenzoate 0.05 10% Sodiumhydroxide qs pH 5.0 ± 0.5 Purified water qs 100.00

The gel at 1.5% (m/m) is prepared according to the same protocol as thegel at 1% (m/m).

b) Foam at 1.5% (m/m): Ingredients Formula (% m/m) Metronidazole 1.50Niacinamide 5.70 Propylene glycol 5.00 Macrogol 400 (PEG 400) 5.00Methylcellulose 0.30 Xanthan gum 0.30 PEG-40 stearate 3.00 Polysorbate80 1.00 Glyceryl monostearate 0.50 Methylparaben 0.15 Propylparaben 0.05Phenoxyethanol 1.00 Mineral oil 6.00 Stearic acid 1.00 Miglyol 6.00Purified water 55.7 Propellant gas qs 100.00

The foam is prepared according to the following procedure:

Aqueous Phase:

1) The water is weighed out into a beaker and the niacinamide, theMacrogol 400, the propylene glycol and the metronidazole are introducedwith stirring using a deflocculator (300 rpm).

2) After complete dissolution of the metronidazole, the aqueous phase isheated to 70° C. and the xanthan gum, the methylcellulose, the PEG-40stearate, the polysorbate 80 and the glyceryl monostearate are added.

3) The methyl paraben is added while maintaining the temperature and thestirring.

Fatty Phase:

1) The stearic acid and the mineral oil are weighed out into a beaker.

2) The mixture is allowed to melt in a water bath at 70° C. and thenhomogenized while maintaining the stirring.

Emulsification:

1) The fatty phase is introduced gently into the aqueous phase withvigorous stirring (900 rpm) using a stator rotor while maintaining thetemperature at 70° C.

2) The mixture is allowed to cool to ambient temperature with gentlerstirring (300 rpm) to a temperature below 50° C.

3) The phenoxyethanol is added and the mixture is allowed to cool toambient temperature with gentle stirring.

4) The mixture is made up with water and homogenized if there has beenevaporation of water during the emulsification.

Packaging:

The oil-in-water emulsion thus obtained is introduced into an aerosolpackaging. After the container has been sealed, the propellant gas isintroduced.

Each patent, patent application, publication, text and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference in its entirety.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1. An aqueous solution of metronidazole, the aqueous solution comprisingan intimate admixture of metronidazole with niacinamide or salt thereofand at least two glycolic cosolvents and devoid of cyclodextrin, whereinthe aqueous solution is prepared by solubilizing the metronidazole withthe niacinamide or salt thereof and the at least two glycolic cosolventsby intimate admixing in the absence of cyclodextrin, wherein the aqueoussolution comprises: 1) metronidazole in a proportion of greater than orequal to 1%, 2) niacinamide in a proportion such that theniacinamide/metronidazole molar ratio is less than 9, and 3) propyleneglycol and at least one polyethylene glycol, as the at least twoglycolic cosolvents.
 2. The aqueous solution as defined by claim 1,wherein the niacinamide/metronidazole molar ratio is less than or equalto 5.5.
 3. The aqueous solution as defined by claim 2, which comprisespropylene glycol and polyethylene glycol
 400. 4. A pharmaceuticalcomposition which comprises an aqueous solution comprisingmetronidazole, niacinamide or salt thereof and at least two glycoliccosolvents in a topically- and pharmaceutically-acceptable medium,devoid of cyclodextrin, wherein said pharmaceutical compositioncomprises: 1) metronidazole in a proportion of greater than or equal to1%, 2) niacinamide in a proportion such that theniacinamide/metronidazole molar ratio is less than 9, and 3) propyleneglycol and at least one polyethylene glycol, as the at least twoglycolic cosolvents.
 5. A regime or regimen for the treatment of adermatological condition/affliction, the regime or regimen comprisingadministering to a subject in need of such treatment, a thus effectiveamount of a pharmaceutical composition comprising metronidazole,niacinamide or salt thereof and at least two glycolic cosolvents in atopically- and-pharmaceutically-acceptable medium, devoid ofcyclodextrin, wherein said pharmaceutical composition comprises: 1)metronidazole in a proportion of greater than or equal to 1%, 2)niacinamide in a proportion such that the niacinamide/metronidazolemolar ratio is less than 9, and 3) propylene glycol and at least onepolyethylene glycol, as the at least two glycolic cosolvents.
 6. Aregime or regimen for the treatment of rosacea, the regime or regimencomprising topically applying onto the affected skin area of a subjectin need of such treatment, a thus effective amount of a pharmaceuticalcomposition comprising metronidazole, niacinamide or salt thereof and atleast two glycolic cosolvents in a topically- andpharmaceutically-acceptable medium, devoid of cyclodextrin, wherein saidpharmaceutical composition comprises: 1) metronidazole in a proportionof greater than or equal to 1%, 2) niacinamide in a proportion such thatthe niacinamide/metronidazole molar ratio is less than 9, and 3)propylene glycol and at least one polyethylene glycol, as the at leasttwo glycolic cosolvents.
 7. The pharmaceutical composition as defined byclaim 4, formulated as a salve, cream, milk, ointment, powder,impregnated pad, syndet, lotion, gel, spray, foam, suspension, stick,shampoo, washing base, microspheres, nanospheres, vesicles, or acontrolled release patch.
 8. The pharmaceutical composition of claim 4,wherein the niacinamide/ metronidazole molar ratio is less than or equalto 5.5.
 9. The pharmaceutical composition of claim 8, which comprisespropylene glycol and polyethylene glycol
 400. 10. The regime or regimenof claim 5, wherein the niacinamide/metronidazole molar ratio is lessthan or equal to 5.5.
 11. The regime or regimen of claim 10, whichcomprises propylene glycol and polyethylene glycol
 400. 12. The regimeor regimen of claim 6, wherein the niacinamide/ metronidazole molarratio is less than or equal to 5.5.
 13. The regime or regimen of claim12, which comprises propylene glycol and polyethylene glycol
 400. 14.The aqueous solution of claim 1, devoid of surfactant.
 15. Thepharmaceutical composition of claim 4, devoid of surfactant.
 16. Theregime or regimen of claim 5, wherein said pharmaceutical composition isdevoid of surfactant.
 17. The regime or regimen of claim 6, wherein saidpharmaceutical composition is devoid of surfactant.
 18. The aqueoussolution as defined by claim 1, wherein the propylene glycol and the atleast one polyethylene glycol are present in a ratio by mass of about1:1.
 19. The pharmaceutical composition of claim 4, wherein thepropylene glycol and the at least one polyethylene glycol are present ina ratio by mass of about 1:1.
 20. The regime or regimen of claim 5,wherein in the pharmaceutical composition, the propylene glycol and theat least one polyethylene glycol are present in a ratio by mass of about1:1.
 21. The regime or regimen of claim 6, wherein in the pharmaceuticalcomposition, the propylene glycol and the at least one polyethyleneglycol are present in a ratio by mass of about 1:1.